Disorders of urinary bladder sensation (discomfort, pain and increased sensitivity) characterize painful bladder syndrome/interstitial cystitis (PBS/IC). PBS/IC is a chronic and debilitating disorder in which urinary frequency and urgency are associated with small bladder volume. Pain, however, is the most common and most troubling symptom in PBS/IC patients and is typical of visceral pain in general - 94% of registrants in a PBS/IC database report pain referred to another pelvic area. Urodynamic studies in PBS/IC subjects confirm that bladder sensations and fullness are perceived at lower intravesical volumes, resulting in a leftward shift of the normal psychophysical function (i.e., bladder hypersensitivity). Because the visceral innervation is unique (organs are innervated by two nerves) and noxious visceral stimuli are unlike noxious tissue-damaging somatic stimuli, peripheral mechanisms of bladder hypersensitivity differ from those of somatic hyperalgesia. Mechanical and/or chemical hypersensitivity of the bladder largely underlies the pain and discomfort experienced by PBS/IC patients, yet the molecules and mediators that confer mechanosensitivity and/or sensitization of bladder sensory neurons and their contribution to urinary bladder pain are poorly understood. The ion channels TRPV1 and P2X3 have been implicated in bladder hypersensitivity. We hypothesize that TRPV1 and P2X3 contribute to mechanotransduction and/or sensitization of the bladder innervation and we will study their contributions: 1) using cystometry to functionally evaluate bladder hypersensitivity, 2) to mechano- and chemo-sensitivity of pelvic nerve and lumbar splanchnic nerve receptive endings in the bladder using an in vitro bladder-nerve preparation, and 3) to whole cell currents and excitability of bladder sensory neurons, identified by content of retrograde tracer. PUBLIC HEALTH RELEVANCE: Relevance: Interstitial cystitis (IC) is a chronic and debilitating disorder, most common in women, and in which pain is the most common and most troubling symptom. IC represents a hypersensitive condition and is difficult to manage. The objective of this research is to determine the mechanisms by which the pain in IC arises and is maintained as a first step in developing better informed and more successful management strategies.